GB2204791A

GB2204791A - Nootropic compositions

Info

Publication number: GB2204791A
Application number: GB08811364A
Authority: GB
Inventors: Kiyoshi Kimura; Fusao Ueda; Masaru Tamura
Original assignee: Nippon Shinyaku Co Ltd
Current assignee: Nippon Shinyaku Co Ltd
Priority date: 1987-05-20
Filing date: 1988-05-13
Publication date: 1988-11-23
Anticipated expiration: 2008-05-13
Also published as: FR2615393A1; DE3816937C2; GB2204791B; GB8811364D0; IT8847980A0; US4874762A; IT1219594B; DE3816937A1

Description

1 P b 22G. 12-1791 Nootropic Agents The present invention relates to

nootropic agents comprising certain triazine derivatives as hereinafter defined As the average age of the population increases, dementia has become an increasingly important disease in elderly people but no therapy therefor has yet been established. Traetments using drugs such as brain metabolism activators, brain circulation improving agents, tranquillizers and cholinergic agents, have been tried but the effect has not been satisfactory.

Several compounds, including aniracetam and pramiracetam, have been developed as nootropics in recent years. However, even these substances are not wholly satisfactory in terms of their effect.

It has now been found, in accordance with the present invention that certain triazine derivatives possess nootropic properties. These triazines have the formula:

1 1 2 - R 1 C T_ ---0 O_ NHCO-C In which R1 is a hydrogen atom, an alkyl group (e.g. a lower, Cl-C6, alkyl group)or an optionally halo-substituted aryl group.

Accordingly,one embodiment of the present invention provides a nootropic pharmaceutical composition comprising, as active ingredient, a triazine derivative of formula (1) in association with a pharmaceutical carrier or diluent. The invention also provides a methodl for the preparation of a nootropic pharmaceutical composition in which there is used as active ingredient a triazine derivative of formula (I). The invention is also concerned with the use of a trazine derivative of formula (1) in the preparation of a nootropic pharmaceutical composition.

3 The triazine derivatives of formula I have been previously described, by us, as having marked anti-ulcer activity; see, for example, Japanese Examined Patent Publication No.4751180. However, as noted above, we have now, quite unexpectedly, found them to posses nootropic action.

Examples of compounds of formula (I) include:

(1) 2-amino-4-nicotinoylamino-6-phenyl-s-triazine, m.p.240-242'C; (2) 2-amino-4-nicotinoylamino-6-(2,4-dichloropheny)-striazine,m.p. 239- 241'C; (3) 2-amino-4-nicotinoylamino-6-(3,4-dichlorophenyl)-striazine; m.p.276279'C; (4) 2-amino-6-methyl-4-nicotinoylamino-s-trazine, m.p.245-247OC; (5) 2-amino-4-nicotinoylamino-s-triazine,m.p.240-241'C; (6) 2-amino-4-nicotinoylamino-6-(4-fluorophenyl)-striazine,m.p. 255-260'C; (7) 2-amino-4-nicotinoylamino-6-pentyl-striazine,m.p. 195-196.5C; (8) 2-amino-4-nicotinoylamino-6-(2-chlorophenyl)-s-triazine, m.p. 224- 22CC; (9) 2-amino-4-nicotinoylamino-6-(4-chlorophenyl)-s-triazine, m.p. 266268OC; - 4 (10) 2-amino-4-nicotinoylamino-6-(3-chlorophenyl)-s-triazine, m.p. 260- 262OC; (11) 2-amino-4-nicotinoylamino-6-(2-iodophenyl)-s-triazine, m.p. 125- 127'C.

(12) 2-amino-4-nicotinoylamino-6-(naphth-l-yl)-s-triazine, m.p. 214-21CC; (13) 2-amino-4-nicotinoylamino-6-(1-naphth-2-yl)-s-triazine, m.p. 242243'C; (14) 2-amino-4-nicotinoylamino-6-(2-fluoro-naphth-3-yl)-striazine, m.p.

(15) 2-amino-4-nicotinoylamino-6-(2-chloro-naphth-3-yl)-striazine, m.p. 229-230C; and (16) 2-amino-4-nicotinoylamino-6-(2-bromo-nappth-3-yl)-striazine, m.p. 245-247C.

The compounds of formula (I) are known per se and can be readily prepared.

The pharmacological activity of formula (1) compounds, i.e. activity against dementia, has been confirmed by thp following tests.

t ill (1) Improvement on Amnesia caused by Scopolamine.

After rats had acquired passive avoidance learning (i.e. acquisition trial), they were given 0.5 mglkg scopolamine intraperitoneally and, immediately thereafter, they were given the test drug orally. After 1 hour, they were again subjected to a passive avoidance test (retention trial).

Positive reaction rates at each dosage of the test drug (i.e. numbers of positive animals/used animals) are given in Table 1.

Table 1.

Test Drug (Compd.No.) MC (5) (6) (7) (16) 118 Positive Reaction Rates Doses (mg/kg) 1 3 10 218618 518 518 518 : p C 0.05 MC stands for 0.5% methylcellulose solution L 1 Thus,the compounds of formula (I) exhibited a significant improvement of amnesia at a dosage of 3 mglkg. The compounds of formula (I) are known to have low toxicity. For example, the compound No.M gave no deaths at all by oral administration at a dosage of 1000 mglkg.

The nootropic agents of the invention may be administered as they are or as pharmaceutical compositions containing, for example, 0.01% to 10'/ (preferably, 0.1% to 5%) of the agent in associaton with a pharmaceutically-acceptable carrier. As carrier, there may be used one or more of solid,semisolid or liquid diluents,fillers and other auxiliary agents. The pharmaceutical composition is desirably in unit dosage form. Pharmaceutical compositions of the invention may be administered orally, by injection, topically or rectally. Needless to say,a dosage form suitable for the administration route should be used. Oral administration is particularly preferred. The dose as nootropic agent is adjusted after taking the status of the patient (e.g. age and body weight), route of administration, type and degree of the disease, and the like into consideration. Usually, these will be administered, to a human adult, 0.1 mg to 30 mg of the effective ingredient per day, preferably from I mg to 10 mg per day. In some cases, a lesser dose may be sufficient while, in other cases, a greater dose may be required. The drug is conveniently administered one to three times a day.

1 - 7 The following are examples of pharmaceutical compositions in with the invention.- Example 1. Tablets were prepared in a conventional manner from 4 mg of 2- amino-4-nicotinoylamino-s-triazine, 50 mg of lactose, 22 mg of corn starch, 5.1 mg of crystalline cellulose, 3.4 mg of hydroxypropylcellulose and 0.5 mg of magnsium stearate.

Claims

Example 2. Fine granules were prepared in a conventional manner from 4 mg

of 2-amino-4-nicotinoylamino-s-triazine, 335 mg of lactose, 144.5 mg of corn starch, 1.5 mg of aqueous silicon dioxide and 15 mg of hydroxypropylcellulose. Claims.

Claims 1. A method of preparing a nootropic pharmaceutical composition in which there is used as active ingredient a triazine derivative of the formula:- R j C) N NNI N .--H (in which R' i s a hydrogen atom; an alkyl group or an optionally halo- substituted arylgroup) or a pharmaceutically acceptable salt thereof.
2.The use of a triazine derivative of formula (I) (as defined in Claim 1) in the preparation of a nootropic pharmaceutical c ornpo sit inn.

1# p 9
3.A nootropic pharmaceutical composition comprising a triazine derivative of formula (I) (as defined in Claim 1) in association with a pharmaceutical carrier or diluent.

Published 1988 at The Patent Office, State House, 56/71 High Holborn, London WClR 4TP. Further copies may be obtained from The Patent OUICa, Sales Branch, St Mary Cray, Orpington, Kent BR5 3RD. Printed by Multiplex techniques ItAl, St Mary Cray, Kent. Con. 1187.